Hypersensitivity Pneumonitis

Hypersensitivity Pneumonitis 

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease caused by the inhalation of an antigen to which the patient is sensitized and hyperresponsive.

Synonyms

• HP
• Extrinsic allergic alveolitis (EAA)
• Bird fancier’s lung
• Farmer’s lung
• Malt worker’s lung
• “Ventilation” pneumonitis
• Maple bark-stripper’s lung
• Sauna taker’s lung
• Hot tub lung

Epidemiology & Demographics

• •Estimates of the prevalence and incidence of Hypersensitivity Pneumonitis vary considerably and depend on the definition and methods used to establish the diagnosis.
• •Clinical presentation depends on the intensity of exposure, environmental conditions, and genetic risk factors that remain poorly understood.
• •More than 300 causative agents have been identified, and the number continues to grow.
• •Causative agents in residential and occupational exposures include birds, mold, humidifiers, fountains, steam irons, dry sausage molds, moldy cheese, contaminated wood, biofilm contained within wind instruments (e.g., trombone, saxophone), and organic and inorganic chemicals, including metalworking fluids.
• •It is likely that genetic factors are involved that result in an exaggerated lung response to an offending agent. The major histocompatibility complex is the most studied thus far.

What are the symptoms of Hypersensitivity Pneumonitis – Physical Findings & Clinical Presentation

• •Presentation is heterogeneous and, until recently, was classified by the clinical presentation as acute, subacute, or chronic HP based on the intensity, frequency, and duration of antigen exposure and symptoms.
  • 1.Acute Hypersensitivity Pneumonitis: Fever, chills, malaise, cough, and dyspnea that occur within 4 to 8 hr of an intense exposure. This flu-like syndrome improves in 24 to 48 hr and can be mistaken for an acute respiratory infection.
  • 2.Subacute Hypersensitivity Pneumonitis: Progressive dyspnea and cough that occurs after weeks or months of sustained low-level exposure or recurrent exposure to an offending antigen.
  • 3.Chronic Hypersensitivity Pneumonitis: Progression of subacute HP, with chronic, progressive dyspnea and cough, fatigue, and weight loss, over months or years of low-level exposure to an offending agent.
• •Because these clinical presentations are not consistently associated with outcomes, Hypersensitivity Pneumonitis is currently classified as fibrotic or nonfibrotic.
• •Physical examination findings include inspiratory crackles and squeaks on lung auscultation, hypoxemia, cyanosis, possibly fever, and clubbing.

What causes this condition?

• •Numerous environmental agents, both at home and in occupational settings.
• •Common sources of antigens: “Moldy” hay, silage, grain, or vegetables; bird droppings or feathers (including those found commonly in down pillows, blankets, and upholstered furniture); low–molecular-weight chemicals (e.g., isocyanates); pharmaceutical products.

Pathogenesis of hypersensitivity pneumonitis (HP).

Chronic and repeated exposure to antigens in genetically susceptible individuals triggers an inflammatory process.

A T-helper 1 (Th1) response predominates in the early stages, whereas Th2 skewing occurs in later stages, both leading to tissue damage from inflammatory propagation and cytokine release.

Lung tissue lymphocytes are increased because of decreased lymphocyte apoptosis and impaired regulatory T cell (Treg) function (mediated by interleukin [IL]-17).

Early inflammatory changes include IgG binding to antigen and complement pathways with macrophage activation and secretion of chemoattractants (CXCL8, CCL5, CCL3) that induce neutrophilic airway infiltration and tissue destruction. 

Differential Diagnosis

Here is the table on the differential diagnosis at different stages of HP.

Stages of Hypersensitivity Pneumonitis

Acute Stages	Chronic Stages
Allergic bronchopulmonary aspergillosis Pulmonary embolism Asthma Aspiration pneumonia Bacterial pneumonia Fungal or mycobacterial pneumonia Bronchiolitis obliterans–organizing pneumonia Eosinophilic pneumonia Churg-Strauss syndrome Wegener granulomatosis	Idiopathic pulmonary fibrosis (IPF) Bronchiectasis Chronic bronchitis Nonspecific interstitial pneumonia (NSIP) Connective tissue–related lung disease Sarcoidosis

Workup

• •Establishing the diagnosis of HP and identifying the offending exposure has treatment and prognostic implications. The diagnosis of HP is based on a combination of exposure history, radiographic findings, bronchoalveolar lavage (BAL), and histologic features.
• •Major diagnostic criteria:
  • 1.Exposure: Compatible clinical features (cough and dyspnea) in the setting of an environmental exposure known to cause HP, temporal relation between exposure and disease, clinical improvement with antigen avoidance. Detailed occupational, hobby, and home exposure history is required, along with a high index of suspicion. Questions should address environmental exposure to grain dusts; animal handling; food processing; cooling towers; fountains; metal-working fluids; symptom improvement away from exposure; pets (particularly birds); hobbies involving chemicals, feathers, or fur; organic dusts; presence of humidifiers, dehumidifiers, or hot tubs/saunas; leaking or flooding indoors; visible fungal growth in living or working environment; and feather pillows, bedding, or upholstered furniture. The below table describes examples of occupational causes of HP. In up to 50% of patients the specific offending exposure may remain unidentified.

Examples of Occupational Causes of Hypersensitivity Pneumonitis

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Occupation	Cause
Farmer	Thermophilic actinomycetes in moldy hay
Metal worker	Contamination of metal-working fluids with microorganisms such as Mycobacteria immunogens or fungi
Worker exposed to humidifiers	Contamination with microorganisms such as protozoa or fungi
Sugarcane worker	Moldy sugarcane (bagassosis)
Maple bark stripper	Fungi
Chicken or turkey worker	Avian proteins
Pharmaceutical worker	Penicillin
Food handler	Soybeans
Office worker	Microorganisms contaminating air conditioners or humidifiers
Swimming pool attendant	Fungal contamination in sprays around pool area
Animal worker	Rat proteins
Mushroom worker	Fungi
Wheat farmer or handler	Weevil-infested flour
Greenhouse worker	Fungi
Workers spraying urethane paint or adhesives/sealants (or less often, other workers using diisocyanate)	Methylene diphenyl diisocyanate, hexamethylene diisocyanate, toluene diisocyanates
Chemical worker using plastics, resins, paints	Trimellitic anhydride

• • Radiographic: A typical or compatible HP pattern on high-resolution CT scan (HRCT). Features of small airway disease, including mosaic attenuation, a three-density pattern of normal lung, ground-glass opacity, air trapping, and centrilobular nodules. Findings most often are present with an upper lobe predominance. Fibrosis, including septal thickening, traction bronchiectasis, and honeycombing, may be present and often spares the lower lobes.
  • 3.BAL: Lymphocytosis >30%. Bronchoscopy with BAL provides useful supportive data in the diagnosis of HP. Usually reveals intense lymphocytosis (typically T cells >40%) of predominantly CD8+ suppressor cells.
  • 4.Histological: A typical or probable HP pattern on transbronchial biopsy or surgical lung biopsy. Poorly formed nonnecrotizing granulomas, giant cells, chronic bronchiolocentric inflammation, airway-centered interstitial fibrosis, absence of alternative diagnosis. In chronic HP, fibrosis can resemble usual interstitial pattern with fibroblastic foci or a nonspecific interstitial pneumonia pattern.
• •HP must be suspected in patients presenting with cough, dyspnea, fever, and malaise. A thorough exposure history and an HRCT of the chest are the two most useful tests to make the diagnosis. BAL lymphocytosis supports the diagnosis. Surgical lung biopsy is especially helpful to achieve a confident diagnosis when HRCT shows a usual interstitial pneumonia pattern.

Laboratory Tests

• •Serum precipitin test for IgG antibodies against offending antigen have a sensitivity and specificity of 83% and 68%, respectively. Asymptomatic patients may have IgG antibodies in serum. HP may occur without a positive precipitin test. When positive, precipitins indicate that the patient has been exposed to the antigen during his or her life. Further exploration to determine if any particular antigen is the cause of the disease is warranted.
• •Lactate dehydrogenase (LDH) is increased and tends to decrease with improvement.
• •Pulmonary function tests: Restrictive ventilatory pattern is typically seen. Decreased FEV1, decreased forced vital capacity, decreased total lung capacity, decreased diffusing capacity, and decreased static compliance.
• •Arterial blood gases show mild hypoxemia (worsens with exercise) and A-a gradient shows slight increase.
• •The role for controlled inhalation provocation test using aerosolized materials of the suspected causative agent has not been established.

Imaging Studies

• •Chest x-ray: Nonspecific; may be normal in early stages.
• •High-resolution chest CT scan: May vary with stage of disease but often includes features of small airway disease, including mosaic attenuation, a three-density pattern of normal lung, ground-glass opacity, air trapping, and centrilobular nodules. Findings most often are present with an upper lobe predominance. The chronic stage may reveal honeycombing, air trapping, and traction bronchiectasis.
  

How is this condition treated?

Nonpharmacologic Therapy

Identification and complete avoidance of exposure to the offending antigen is the cornerstone of treatment. Avoidance can lead to resolution of acute and subacute HP, as well as to stability and improved survival in chronic HP.

Acute General Treatment

• •Corticosteroids accelerate initial recovery for acute and subacute HP, but may have no effect long term (from a controlled study in farmer’s lung).
• •Prednisone 0.5 mg/kg for 1 to 2 wk then tapered over 4 wk.

Chronic Treatment

• •For subacute and chronic HP, steroid-sparing immunosuppression with mofetil mycophenolate or azathioprine, which are better tolerated than prednisone, should be considered for maintenance treatment. Although there are no randomized controlled trials, a retrospective study showed that treatment with either agent was associated with a 4% improvement in DLCO at 1 yr.
• •Once the offending antigen exposure has been remediated, and there is improvement or stabilization of symptoms and pulmonary function tests, consider gradual tapering off of immunosuppression.
• •For chronic HP with progressive fibrosis despite antigen avoidance and immunosuppression, switching to or adding antifibrotic therapy could be considered. Nintedanib and pirfenidone, medications with antifibrotic and antiinflammatory properties, have been shown to slow the progression of progressive fibrosing interstitial lung disease in randomized clinical trials. Nintedanib has FDA approval.

Disposition/Prognosis

Prognosis is good for patients with acute or subacute HP, especially if the offending antigen is identified. Antigen exposure alone or with immunosuppression can lead to improvement.

Prognosis is worse for patients with chronic HP; approximately 25% die within 5 yr in a cohort of pigeon breeders’ lung disease.

Chronic HP is associated progressive pulmonary fibrosis, development of pulmonary hypertension, and right heart failure. Honeycombing on HRCT and clubbing indicate advanced disease with poor survival.

Referral

• •Pulmonologist: To identify potential exposures and educate patient on its avoidance, establish the diagnosis in multidisciplinary conference and develop a treatment and monitoring strategy.
• •Thoracic surgeon for surgical lung biopsy.
• •Lung transplant center: To consider lung transplant candidacy. Patients with chronic HP who undergo lung transplant have excellent survival, reported at 89% at 5 yr in a single center series; better than survival after lung transplant for IPF. Can recur in the transplanted lung with exposure to the offending antigen.

 Pearls & Considerations

• •HP occurs more frequently in nonsmokers than smokers (likely from an immunosuppressive effect).
• •Chronic HP may be difficult to distinguish from IPF. Diagnosis often made in the lung explant at the time of transplant.

Suggested Readings

• Adegunsoye A., et al.: Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis. ERJ Open Res 2017; 3: pp. 00016-2017.
• Fernández Pérez E.R., et al.: Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 2013; 144 (5): pp. 1644.
• Flaherty K., et al.: Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med 2019; 381 (18): pp. 1718-1727.
• Kern R.M., et al.: Lung transplantation for hypersensitivity pneumonitis. Chest 2015; 147 (6): pp. 1558-1565.
• Maher T., et al.: Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2020; 8 (2): pp. 147-157.
• Morisset J., et al.: Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest 2017; 151 (3): pp. 619-625.
• Morisset J., et al.: Identification of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modified Delphi survey. Am J Respir Crit Care Med 2018; 197 (8): pp. 1036-1044.
• Raghu G., et al.: Diagnosis of hypersensitivity pneumonitis in adults: an official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202 (3): pp. e36-e69.
• Selman M.: Hypersensitivity pneumonitis. In Schwarz M.I., King T.E. (eds): Interstitial lung disease. 2011. Elsevier,
• Tsutsui T., et al.: The amount of avian antigen in household dust predicts the prognosis of chronic bird-related hypersensitivity pneumonitis. Ann Am Thorac Soc 2015; 12 (7): pp. 1013-1021.